This invention relates to a new chemokine, neurotactin, and methods of preparing and using neurotactin.
Chemokines are proteins involved in the activation and chemotaxis of leukocytes. They are believed to be important mediators of inflammation (Baggiolini et al., Immunology Today 15:127, 1994). Chemokines have been divided into three families based on the number and arrangement of their cysteines and disulfide bonds. Proteins in the C-X-C family and the C-C family have two disulfide bonds. Proteins in the third family, which is represented by a molecule called lymphotactin, have only one disulfide bond.
In chemokines of the C-X-C family, one amino acid separates the first two cysteines. Chemokines in this family are thought to be involved in the chemotaxis of neutrophils, induction of changes in cell shape, transient increase of intracellular calcium, granule exocytosis, and respiratory burst. Interleukin-8 (IL-8), neutrophil activating protein-2 (NAP-2) and granulocyte chemotactic protein (GCP) belong to this class. All known C-X-C chemokines have been mapped to human chromosome 4 and mouse chromosome 5.
In chemokines of the C-C family, the first two cysteines are adjacent to one another. Members of this family are chemotactic for monocytes, but not neutrophils. Recent studies have shown that they are capable of activating basophils and eosinophils. Proteins belonging to the C-C class of chemokines include monocyte chemotactic proteins 1, 2, and 3 (MCP-1, MCP-2, and MCP-3), RANTES, and macrophage inflammatory proteins .alpha. and .beta. (MIP-1.alpha. and MIP-1.beta.). Recently, three additional C-C chemokines, MIP-3, MIP-4, and MIP-1.gamma., have been described (see PCT Publication No. WO 95/17092). All known C-C chemokines have been mapped to human chromosome 17 and mouse chromosome 11.
An example of a third class of chemokine has also been identified. This chemokine, lymphotactin, was isolated from progenitor T lymphocytes. Lymphotactin is chemotactic to lymphocytes (Kelner et al., Science 266:1395, 1994). Unlike the chemokines of the C-C and C-X-C families in which two disulfide bonds stabilize the protein, lymphotactin has only one disulfide bond. Lymphotactin was mapped to human and mouse chromosome 1.
A variety of cell types are involved in the various inflammatory states. For example, acute infiltrates found after bacterial infection are mainly neutrophilic, while mononuclear cells predominate after infection by an intracellular pathogen. Basophils and eosinophils dominate in both immediate-type allergic response and autoimmune diseases. Increased understanding of the regulation of these various cell types by chemokines will facilitate the development of more effective therapies for disorders related to inflammation.
Brain inflammation is only partially understood. It appears that the brain regulates its own immune response rather than being an immunological privileged organ (Trevor et al., Immunology Today 15:566, 1994). Inflammatory cytokine production in the brain is initiated by infiltrating T cells but longer term inflammation is dependent on CNS resident cells, such as microglial cells.